Process for the production of 6-chloro-3-keto-deta steroid compounds



3,076,823 PROCESS FOR TEE PRODUCTION F fi-CHLURO-li- KE'ifl-A STERQEDCOMPUUND Howard J. Ringold, Shrewsbury, Mass, and Franc sco Alvarez andJames C. Orr, Mexico City, Mexico, assignors,by mesne assignments, toSyntex Corporation, a corporation of Panama No Drawing. Filed July 3,1961, Ser. No. 121,331 Claims. (Cl. Mil-$97.4)

The present invention relates to a novel process for the production ofcyclopentanophenanthrene compounds.

More particularly the present invention relates to a process for theproduction of 6-chloro-3-keto-A steroid compounds especiallyof thepregnane and androstane series. Compounds of the character set forth arevaluable therapeutic agents. Thus 17a-acetoxy-6-chloro-Apregnadiene-El,20-dione is an extremely valuable progestational agent,6-chloro-6-dehydrocortisone is a valuable anti-inflammatory agent etc.In general, however, the methods for the introduction of the 6-chlorogroup have been complicated and have resulted in relatively low ields. yIn accordance with the present invention the surprising discovery hasbeen made that when a A -3-keto steroid is reacted with chromylchloride, there is a selective reaction with the A -double bond toproduce the corresponding 6-chloro-7-hydroxy-3-keto-steroid. Dehydrationof this last mentioned compound with strong acid then gave the desired6-chloro-3-keto-A -steroid in high yield.

The novel process of the present invention is therefore exemplified bythe following equation:

Referring to the above equation, a 3-keto-A -steroid' preferably of thepregnene or androstene series (I) is reacted with chromyl chloride togive the corresponding 6B-chloro-7a-hydroxy-3-keto-A -steroid (II).Typical steroid starting materials include d -androstadien-l7fi-ol-3-one (6-dehydro-testosterone), A androstadien 3,17-

dione (Gdehydro-androstendione), A -pregnadiene-3,20-

dione (6-dehydro-progesterone). The 17-acetate of Apregnadiene-l7u-ol-3,20-dione (6-dehydro 17a-acetoxyprogesterone)6-dehydro-cortisone, o-dehydro Reichsteins 'S etc. The last twocompounds mentioned may be used in the form of their knownbismethylenedioxy derivatives or 2l-estersin order to prevent sidereactions with the side chain and provide higher yields. I

For the first step of the reaction preferably the sterold and reagentare dissolved in an inert organic solvent such ,as glacial acetic acid,chloroform, carbon tetrachloride,

benzene, methylene dichloride, tetrahydrofuran etc. The temperature ofthe reaction is not especially critical and may vary from the freezingpoint to the boiling point of thesolvent used. In general, however, forhighest yields temperatures between -1 0 C. and +10" C. are de sirable.The time of reaction may also be widely varied as for example from 15minutes to 24 hours. The shorter time of reaction is, as may beunderstood, best used with higher reaction temperatures and longer timeswith lower temperatures. Preferablya reaction time of 1 to 5 hours at atemperature of from -10 C. to 10 C. is used. The chromyl chloride ispreferably use-d in molar excess, that is, in an amount 1.5 times to 10times the starting steroid. About 2 to 5 mols for each mol of steroid isan especially desirable amount.

The second step may be practised with or without the isolationof theintermediate 6fi-chloro-7a-hydroxy compound. Thus the reaction mixtureof the first step may be treated directly with acid to give a reactionmixture containing the 6-ch1oro-3-keto-A -steroid which may then bepoured into Water and the 6-chloro-3-ketoA compound extracted andpurified. Secondly, the reaction mixture of the first step may be pouredinto water, extracted with an organic solvent and the solvent solutionused for the second step reaction. Thirdly, the product of the firststep may be completely isolated and then redissolved in an organicsolvent and dehydrated with acid.

Suitable organic solvents may be used for the second dehydration stepincluding acetic acid, chloroform, methylene dichloride, ethyl acetate,acetone, etc. Mineral acids or strong organic acids are' preferred forthe dehydration; typical acids are p-toluenesulfonic acid, hydrochloricacid, hydrobromic acid, sulfuric acid, etc. Best results were obtaiuedbythe use of hydrochloric or hydrobromic acid in chloroform. These lastacids could be used in either concentrated aqueous form or by passinghydrogenchloride or hydrogen bromide into the steroid solution. Thequantity of acid used and the temperature and/ or time of reaction isnot critical. Preferably room temperature or above up to the boilingpoint of the solvent is used for a periodof time of from 30 minutes tothree hours. However, reflux temperature may be used. Where gaseous HClor HBr is used the solution is saturated therewith. Where concentratedhydrochloric or hydrobromic acid is used, sufiicient acid is used tobring the pH of the reaction solution substantially below neutralityi.e. to a pH below 3.5.

The following specific examples serve to illustrate but are not intendedto limit the present invention:

Example I point of 133- C.; [11],; +2 (CHCl Amax. 241mm log 5:2.85.Yield: 78%.

Example II 2 g. of the foregoing chlorohydrin were added to a mixture of50 cc. of acetic acid and 5 cc.of concentrated hydrochloric acid whihhad previously been brought to a temperature of 70 C. One hour after theaddition of the steroid, the solution was poured into water andextracted with ethyl acetate. 'The organic extract was washed withwater, and evaporated to dryness. Crystallization from ethanol afforded6-chloro-6-dehydro-17aacetoxy-progesterone.

- 1 liter of water, and extracted with ether. was washed successivelywith water, sodium bisulfite soluleft at 10 C. for 2 /2 hours. one literof water, and extracted with ether. The extract aoreeae 3 This compoundhas a melting point of 210-12 C; [(11 --2 (CHCl A max.=284- m log6:4.34. Yield; 85%.

Example III 3 g. of 6-dehydro-l7u-acetoxy-progesterone in 200 ml. ofchloroform was cooled to C. A solution of 5 molar equivalents of chromylchloride in 27 cc. of chloroform was added in one lot, the mixtureshaken and left at 0 C. for 3 hours. Then the reaction mixture was addedwhile stirring to a mixture of 50 cc. of acetic acid and 5 cc. ofconcentrated hydrochloric acid and heated to a temperature of 70 C. Onehour after the addition, the mixture was poured into water and extractedwith ethyl acetate. The organic extract was washed with water, andevaporated to dryness. Crystallization from ethanol afforded6-chloro-6-dehydro-l7or-acetoxy-progesterone.

Example IV 3 g. of G-dehydro-17u-acetoxy-progesterone in 200 ml.

of chloroform was cooled to 0 C. A solution of 5 molar equivalents ofchromyl chloride in 27 cc. of chloroform was added in one lot, themixture shaken and left at 0 C. for 3 hours. Then it was poured into oneliter of water, and extracted with ether. The extract was washedsuccessively with water, sodium bisulfite solution,

Example V 3 g. of 6-dehydro-17or-acetoxy-progesterone in 200 ml.

' form was added in one portion, the mixture shaken and left at 10 C.for 5 hours. Then it was poured into The extract tion, and water.Evaporation to dryness and crystallization of the residue from ethylacetate yielded 6fi-chloro- 7u-acetoxy-proesterone. Yield 75%.

Example VI 3 g. of 6-dehydro-17e-acetoxy-progesterone in 200 ml. ofchloroform was cooled to 10 C. A solution of 5 molar equivalents ofchromyl chloride in 27 cc. of chloroform was added in one batch, themixture shaken and Then it was poured into was washed successively Withwater, sodium bisulfite solution, and water. Evaporation to dryness andcrystallization of the residue from ethyl acetate yielded 6,8-chloro-7a-hydroxy-17a-acetoxy proesterone. Yield 76%.

Example VII 2 g. of the chlorohydrin obtained according to Example I,were added to a mixture of 50 cc. of acetic acid and 5 cc. of 47%hydrobromic acid which had previously been brouht to a temperature of 70C. One hour after the addition of the steroid, the solution was pouredinto water, and extracted with ethyl acetate.

The organic extract Was washed with water, and evaporated to dryness.Crystallization from ethanol afforded 6-chloro-6- dehydro-lh-acetoxyprogesterone.

Example I, were added to a mixture of 50 cc. of acetic acid and 5 cc. ofconcentrated sulfuric acid which had previously been brought to atemperature of 70 C. One hour after the addition of the steroid, thesolution was poured into water and extrated with ethyl acetate. Theorganic extract was washed with water, and evaporated to dryness.Crystallization from ethanol afforded6-chloro-6-dehydro-17ot-acetoxy-progesterone.

Example IX Example X Following the procedure described in Example I,there were treated the starting materials listed below, affording thecorresponding indicated intermediates which upon treatment in accordancewith Example II, afforded the respective products hereinafter set forth.

Starting compound Intermediate Product A -androstadien-17B- ol-3-one.

A -sn lrostadiene-3,

17-dione.

A -pregnadlene-3,20-

dione.

A -pregnadien-l7aol-3,20-dione-17- acetate.

17,20;20,2l-bismethylenedioxy-G-dehydrocortisone.

17,2O;20,21-bisn1ethylenedioxy-G-dehydrofi-chloro-A-pregnadiene-3,20-dione.

fi-chloro-N- -pregnadien-17a-ol-3,20 dione-l7-acetate.

17,20;20,21-bisn1ethylcnedioxy-G-chlorofi-dehydro-cortisone.

17,20;20,21-bisrnethylenedioxy-fi-chloro- G-dehydro-Reichsteins S.

Reichsteins S. 7a-hydroxy Reichsteins S.

We claim: 1. A process for the production of 6-chloro-3-keto-A steroidsselected from the group consisting of the androstane and pregnane seriescomprising reacting the correspending 3-keto-A -steroid with chromylchloride and thereafter dehydrating the thus formed6fl-chloro-7uhydroxy-3-keto-A -steroid with a strong acid.

2. In a process for the production of 6-chloro-3-keto- M' -steroidsselected from the group consisting of the androstane and pregnane seriesthe step comprising reacting the corresponding 3-keto-A -steroid withchromyl chloride. 1

3. The process of claim 2 wherein the reaction is conducted in an inertsolvent at a temperature range from 10 C. to 10 C.

4. The process of claim 2 wherein the reaction is conducted in an inertsolvent at a temperature range from. 10 C. to 10 C.

5. The process of claim 2 wherein the reaction is effected with anexcess of chromyl chloride.

6. The process of claim 5 wherein the reaction is effected at -10 C. to10 C. from 1 to 5 hours.

7. In a process for the production of 6-chloro-3-keto- A steroidsselected from the group consisting of the androstane and pregnane seriesthe step comprising reacting the corresponding 3keto-A -steroid with 1.5to .10 mols of chromyl chloride.

8. The process of claim 1 wherein 2 to 5 mols of chromyl chloride areemployed.

9. A process for the production of 17u-acetoxy-6- chloro-A-pregnadiene-3,20-dione comprising reacting l7ot-acetoxy-A-pregnadiene-3,2O-dione with chromyl chloride and thereafter dehydratingthe thus for-med 17w;

5 6 ncetoxy 6,8 chloro-7a-hydroXy-A -pregnene-3,ZO-dione reacting17a-acetoxy-A -pregnadiene-3,20-dione at 0 C. with an acid selected fromthe group consisting of hydroin an inert solvent with 5 molarequivalents of chromyl chloric acid and hydrobromic acid. chloride.

10. In a process for the production of 17a-acetoxy-6- chloro-A-pregnadiene-3,20-di0ne the step comprising 5 No references cited.

UNITED STATES PATENT OFFICE CERTiFICATE ()F (30 REHUN Howard J, Ringoldet ala It is hereby certified that error a ent requiring correction andthat the sa corrected below.

ppears in the above numbered patid Letters Patent should read as Column4 line 60, after "-10 C,

to 10 6,." insert ,for a period of time of l to 5 hour-sq Signed andsealed this 20th day of August 1963,

(SEAL) Attest:

ERNEST w. SWIDER DAVID LADD Attesting Officer Commissioner of Patents

1. A PROCESS FOR THE PRODUCTION OF 6-CHLORO-3-KETO-$4,6STERIODS SELECTEDFROM THE GROUP CONSISTING OF THE ANDROSTANE AND PREGNANE SERIESCOMPRISING REACTING THE CORRESPONDING 3-KETO-$4,6-STEROID WITH CHROMYLCHLORIDE AND THEREAFTER DEHYDRATING THE THUS FORMED6B-CHLORO-7AHYDROXY-3-KETO-$4-STEROID WITH A STRONG ACID.